Viruses offer a great potential as source of vectors for gene therapy and for gene vaccination. Several viruses are currently used for gene therapy, both experimental and in man, including RNA viruses (gamma-retroviruses and lentiviruses) and DNA viruses (adenoviruses, adeno-associated viruses, herpes viruses and poxviruses). The choice of a virus vector is dictated by several factors, such as the time during which transgene expression is required, the target cells that have to be transduced, whether the target cell is dividing or not, the risk related to multi-insertional events and the risk of inducing a vector-orientated immune response. For a recent review see, e.g., Flotte (2007), J. Cell. Physiol. 213, 301-305.
Gene therapy is now being considered for the treatment of an increasing number of diseases. These include: (1) autosomal recessive single gene disorders such as cystic fibrosis, haemophilia A and B, chronic granulomatous disease, X-linked severe combined immunodeficiency and familial hyperlipemia; (2) autosomal dominant syndromes; (3) many forms of cancer; (4) infectious diseases; (5) chronic inflammatory syndromes, and; (6) intractable pain. In the future, the therapy of diseases associated with multiple defects or pathogenetic mechanisms, such as diabetes mellitus, may also become feasible.
Gene vaccination has been developed to cope with the poor protection conferred by soluble proteins of a number of pathogens, including viruses such as the human immunodeficiency virus (HIV). It was thought that intracellular delivery of antigens could direct efficient processing into both major histocompatibility complexes (MHC) class I and class II for improved activation of CD8+ and CD4+ T cells, respectively.
The host immune response towards viral vector proteins was soon recognised as a limiting factor in gene therapy. Cells transduced with viral vectors elicit specific T cells, which lead to inflammation and cell lysis, and thereby aborting transgene expression. The results of a recent anti-HIV gene vaccination trial using recombinant adenovirus vectors expressing the HIV gag, pol or Nef gene were reported by Sekaly (2008), J. Exp. Med., 205, 7-12. Surprisingly, it was shown that the presence of a pre-existing immune response towards viral vector proteins had detrimental results on the outcome of vaccination. Thus, in both situations (i.e., either a pre-existing immune response or no pre-existing immune response) the immune response towards vector-related proteins appear to be ominous.
The immune response towards adenovirus provides one of the best examples of this, as vectors derived from adenovirus are used in the setting of both gene therapy and gene vaccination. Adenovirus is highly immunogenic in man and mammals. Upon injection, adenoviruses elicit an acute innate immune response, which results in inflammation and cytotoxicity, which is often transient. This response, however, triggers an adaptive response that leads to the activation of CD4+ and CD8+ T cells. This is observed even with vectors from which most immunogenic proteins have been removed.
The adaptive immune response to adenovirus involves several components: specific antibodies, CD4+ and CD8+ T cells. Viral proteins are processed and presented by host antigen-presenting cells (APC) in the form of peptides bound to (MHC) of class I and II. Thus, such presentation results in activation of specific T cells belonging to the CD8+ or CD4+ subtype, respectively. The function of CD8+ T cells is to lyse cells expressing virus-derived MHC class I peptides. The function of CD4+ T cells is multifaceted: helping B cells to mature and transform into antibody-forming cells, helping CD8+ T cells to acquire full maturation and development of an inflammatory environment. As such, CD4+ specific T cells play a central role in the elaboration of a virus-specific immune response.
Adenoviruses are ubiquitous and more than 50 serotypes have been described. Many subjects are therefore already immunised, which limits the use of vectors derived from such viruses.
Accordingly, in the setting of gene therapy as well as of gene vaccination, it is highly desirable to find ways to prevent and/or suppress immune responses to viral vector proteins.